The caspase-8 inhibitor FLIP promotes activation of NF-κB and Erk signaling pathways

Kataoka, Takao; Budd, Ralph C.; Holler, Nils; Thome, Margot; Martinon, Fabio; Irmler, Martin; Burns, Kimberly; Hahne, Michael; Kennedy, Norman J.; Kovacsovics, Magdalena; Tschopp, Jürg

doi:10.1016/s0960-9822(00)00512-1

Cited by 527 publications

(530 citation statements)

References 37 publications

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“…FLIP protein can also protect cells from TNF␣-mediated apoptosis (33), and, consistently, RA FLS are completely resistant to TNF␣-mediated apoptosis unless NF-B activation is blocked (34). On the other hand, TNF␣ and Fas receptor activation induces NF-B translocation, which leads to increased FLIP expression (35,36). This NF-B loop of Fas signaling may protect cells from Fas-mediated cell death, resulting in proinflammatory and survival, rather than cytotoxic, effects of death receptor stimulation (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Down‐regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas‐mediated apoptosis

Palao¹,

Santiago²,

Galindo³

et al. 2004

Arthritis & Rheumatism

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Section: Discussionmentioning

confidence: 99%

Down‐regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas‐mediated apoptosis

Palao¹,

Santiago²,

Galindo³

et al. 2004

Arthritis & Rheumatism

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“…A putative role for p53 in the proliferative defect of T cells lacking FADD function 19 has not been confirmed. 18 Evidence that FADD, caspase-8 15,20 and cFLIP [21][22][23] promote T-cell activation by increasing stimulation of NF-kB and c-jun N-terminal kinase (JNK) was not substantiated in other studies. 12,18 Rafts are specialised microdomains, located in the plasma membranes of cells, which have the ability to include or exclude signalling proteins and aggregate in response to various stimuli, thus serving as platforms for signalling complexes.…”

Section: Introductionmentioning

confidence: 91%

Modifications and intracellular trafficking of FADD/MORT1 and caspase-8 after stimulation of T lymphocytes

et al. 2004

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The adaptor protein FADD/MORT1 is essential for apoptosis induced by 'death receptors', such as Fas (APO-1/CD95), mediating aggregation and autocatalytic activation of caspase-8. Perhaps surprisingly, FADD and caspase-8 are also critical for mitogen-induced proliferation of T lymphocytes. We generated novel monoclonal antibodies specific for mouse FADD and caspase-8 to investigate whether cellular responses, apoptosis or proliferation, might be explained by differences in post-translational modification and subcellular localisation of these proteins. During both apoptosis signalling and mitogenic activation, FADD and caspase-8 aggregated in multiprotein complexes and formed caps at the plasma membrane but they did not colocalise with lipid rafts. Interestingly, mitogenic stimulation, but not Fas ligation, induced a unique post-translational modification of FADD. These different modifications may determine whether FADD and caspase-8 induce cell death or proliferation.

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“…Functional inactivation of the adaptor protein FADD leads to defective T and B cell proliferation in mice [12,[16][17][18]. Such a proliferative rather than apoptotic pathway might originate from an activated death receptor like CD95 and may be transmitted through FADD and c-FLIP, leading to the activation of the NF-jB and Erk transcriptional pathways [19][20][21][22]. This model is supported by transgenic mice that overexpress FLIP L in T cells [23].…”

Section: Molecular Immunologymentioning

confidence: 96%

“…This discrepancy could again be due to differences in the expression level of the FLIP L transgene. However, there are also other data supporting a pro-proliferative function of FLIP L , which has been reported to mediate the activation of NF-jB (by binding to TRAF and RIP) and Erk (by recruiting Raf-1; [22]), although the genetic FLIP -/-knockout provides evidence that NF-jB activation occurs independently of FLIP [9]. The FLIP -/-knockout is embryonic lethal, but it would be interesting to analyze the proliferative capacity of T cells in RAG2 -/-mice reconstituted with a FLIP -/-hematopoietic system.…”

Section: Decreased Proliferative Capacity Of Lck Flip S -Transgenic Tmentioning

confidence: 98%

Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

et al. 2005

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The cellular homologues of the viral anti-apoptotic v-FLIP proteins exist as a long (c-FLIP L ) and a short (c-FLIP S ) splice variant. While c-FLIP S and v-FLIP are composed solely of two death effector domains, c-FLIP L contains an (inactive) caspase-like domain in addition to these two death effector domains, thereby structurally resembling proCaspase-8. Both c-FLIP L and c-FLIP S suppress apoptosis by inhibiting Caspase-8 activation, although at different levels of pro-Caspase-8 processing. To analyze the consequences of deregulated c-FLIP S expression in vivo, we established lck FLIP Stransgenic mice overexpressing the transgene in thymocytes and in mature T cells. As expected, CD95L-induced apoptosis was impaired in lck FLIP S -transgenic T cells, indicating the functionality of the FLIP S transgene. Remarkably, activation-induced cell death of transgenic T cells was unaffected, despite the observed inhibition of CD95-induced T cell death. Thymic and splenic cell numbers as well as CD4/CD8 cellularity were normal in lck FLIP S -transgenic animals, which in contrast to CD95-deficient mice do not accumulate Thy1 + B220 + CD4 -CD8 -peripheral T cells. c-FLIP S overexpression leads to a significant decrease in activation-induced T cell proliferation in vitro. Despite the capacity of FLIP S to inhibit CD95-induced apoptosis, T cell lymphomagenesis is not observed in lck FLIP S -transgenic mice. Interestingly, the Vb8 + memory T cell pool is enlarged upon staphylococcal enterotoxin B injections, suggesting a specific in vivo function for FLIP S in the maintenance of restimulated T cells. IntroductionAmong many anti-apoptotic regulatory proteins, the Caspase-8-inhibitory FLIP molecule has been studied intensively. Originally detected in different viruses, c-FLIP was eventually identified as the cellular homologue of the v-FLIP proteins ([1, 2] and references herein). Several spliced isoforms of c-FLIP have been characterized, two of which are expressed as proteins: c-FLIP L , the full-length 55-kDa form of c-FLIP, comprises two Nterminal death effector domains (DED) and an enzymatically inactive caspase domain, thereby structurally resembling . c-FLIP S is a shorter 26-kDa form of c-FLIP and, like v-FLIP, contains only the two DED.A functional pro-apoptotic death-inducing signaling complex (DISC) is usually assembled by recruitment of the adaptor protein FADD to the activated CD95 receptor via death domain interactions [3]. Due to binding of their DED, FADD then associates Caspase-8 Molecular immunologyThe first two authors contributed equally to this work. [2,5]. Recruitment of both c-FLIP L and c-FLIP S to the activated intracellular CD95 receptor complex by FADD has been demonstrated, and both proteins are able to inhibit CD95-induced apoptosis as well as cell death mediated by other death receptors [6]. It has even been suggested that c-FLIP S rather than c-FLIP L may be the prime inhibitor of CD95-mediated apoptosis in T cells [7]. Nevertheless, a recent study showed that whereas high levels of c-FLIP L o...

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The caspase-8 inhibitor FLIP promotes activation of NF-κB and Erk signaling pathways

Abstract: We provide evidence that FLIP is not simply an inhibitor of death-receptor-induced apoptosis but that it also mediates the activation of NF-kappaB and Erk by virtue of its capacity to recruit adaptor proteins involved in these signaling pathways.

Cited by 527 publications

References 37 publications

Down‐regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas‐mediated apoptosis

Down‐regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas‐mediated apoptosis

Modifications and intracellular trafficking of FADD/MORT1 and caspase-8 after stimulation of T lymphocytes

Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

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The caspase-8 inhibitor FLIP promotes activation of NF-κB and Erk signaling pathways

Abstract: We provide evidence that FLIP is not simply an inhibitor of death-receptor-induced apoptosis but that it also mediates the activation of NF-kappaB and Erk by virtue of its capacity to recruit adaptor proteins involved in these signaling pathways.

Cited by 527 publications

References 37 publications

Down‐regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas‐mediated apoptosis

Down‐regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas‐mediated apoptosis

Modifications and intracellular trafficking of FADD/MORT1 and caspase-8 after stimulation of T lymphocytes

Transgenic overexpression of the Caspase‐8 inhibitor FLIPshort leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

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Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection